Adenosine 3',5'-monophosphate (cyclic AMP) and other cyclic nucleotides play an essential role in regulating basic biological processes, and there is increasing evidence suggesting their involvement in the etiology of several disease states including cancer. Cyclic AMP is abnormally low in certain malignant cells and can revert the abnormal characteristics of malignant cells toward normal. The general objective of the proposed research program is to find pharmacologic agents which can selectively alter the concentration of cyclic AMP in specific organs and discrete cell types. To this end, our immediate goal is to isolate and characterize the various forms of the enzyme which hydrolyzes cyclic AMP, phosphodiesterase, in normal cells and in different types of cancer cells. Once we have established the type and distribution of phosphodiesterase in these cells, we will search for compounds that will selectively alter the activity of the dominant form of the phosphodiesterase isozyme in the cancer cells. We will then measure the level of cyclic AMP in these cells and in normal tissues after administering the specific phosphodieterase inhibitors. Ideally, the concentration of cyclic AMP should increase only in the cancer cells, leaving the normal cells unaffected. Finally, in order to determine whether these results have any clinical significance, we will administer the inhibitor to animals with various forms of cancer to determine whether the course of the malignancy can be altered without affecting the normal function of the animal. Specifically, we will study the properties of the phosphodiesterases of normal leukemic lymphocytes and we will try to find selective pharmacologic agents which will inhibit a specific isozyme of phosphodiesterase in the leukemic lymphocytes. This drug should raise the intracellular concentration of cyclic AMP in these cells, thereby arresting their growth. We hope this type of study will provide a new and effective approach toward inhibiting the growth of malignant cells.